Lilly Pulls Heart Drug

In a blow to its late-stage drug pipeline, Eli Lilly & Co. is pulling the plug on evacetrapib after the cholesterol drug failed to improve cardiovascular outcomes in a huge patient study. In addition to sending Lilly’s stock down by nearly 9% last week, the setback shook the larger cardiovascular drug development field as watchers questioned the drug’s mechanism of action.

Evacetrapib is part of a class of compounds that raise levels of high-density lipoprotein—or “good” cholesterol—by blocking cholesteryl ester transfer protein (CETP). The strategy differs from statin drugs, which decrease levels of low-density lipoprotein—the “bad” cholesterol. In both cases the goal is to avoid heart attacks and strokes by reducing arterial plaque.

But early data from a Phase III clinical trial that enrolled more than 12,000 people suggested evacetrapib was not effective in reducing cardiovascular events. Lilly will take a $90 million charge in its fourth-quarter earnings as it shuts down the program. Had it been successful, evacetrapib was expected to hit the market in 2018 and rack up annual sales of as much as $4 billion. Now, analysts are questioning the health of Lilly’s new drug pipeline.

Lilly isn’t the only company to have been done wrong by the CETP target. In one of the most notable failures in the drug industry’s history, Pfizer shelved its CETP inhibitor torcetrapib in 2006 after it increased, rather than decreased, the risk of death in a 15,000-person study. Later studies revealed that the drug also failed to slow down the accumulation of plaque in heart arteries.

After the Pfizer bombshell, companies developing CETP inhibitors incorporated more safety and mechanistic studies into their programs. Merck & Co., Roche, and Lilly plowed ahead with CETP inhibitors that they said overcame the safety liability in Pfizer’s compound.

But Roche ended development of its CETP inhibitor, dalcetrapib, in 2012 because of lack of efficacy. With Lilly now reporting a safe, but ineffective, molecule, many are questioning whether the approach is flawed.

“The commercial prospect of the entire CETP inhibitor class is again in doubt, with three out of four major CETP outcome trials having failed,” Leerink stock analyst Seamus Fernandez said in a note to investors.

Merck continues to push forward with anacetrapib, which is currently being tested in a Phase III study that has enrolled more than 30,000 people. Amgen, meanwhile, paid $300 million last month to buy Dezima Pharma, which has a CETP inhibitor in Phase IIb studies.

John LaMattina, a senior partner at the health care venture firm PureTech Ventures, was head of R&D at Pfizer during the torcetrapib setback. He suggests Amgen should scrap its program rather than risk a hefty investment in large studies that seem destined to fail.